Background: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) unresponsive to intravesical bacillus Calmette–Guérin (BCG). TAR-200 is an intravesical drug delivery system for local continuous release of gemcitabine within the bladder. The current study will assess the rate of complete response (CR) upon treatment with TAR-200 + systemic cetrelimab (CET [anti–PD-1 antibody]), TAR-200, and CET in BCG-unresponsive participants with HR-NMIBC who are ineligible for or decline radical cystectomy (RC). Methods: SunRISe-1 (NCT04640623) is an open-label, parallel-group, multicenter phase 2b study designed to assess the efficacy and safety of TAR-200 + CET, TAR-200 alone, and CET alone in participants with BCG-unresponsive HR-NMIBC. Eligible participants are aged ≥ 18 years with ECOG PS 0, 1, or 2 and recurrent or persistent histologically confirmed HR-NMIBC (carcinoma in situ) with or without papillary disease (T1, high-grade Ta), who have been diagnosed within 12 months of last BCG treatment and are ineligible for or declined RC. Participants (N≈200) are randomized 2:1:1 to receive TAR-200 + CET (Cohort 1, n≈100), TAR-200 (Cohort 2, n≈50), or CET (Cohort 3, n≈50). In Cohorts 1 and 2, participants receive intravesical TAR-200 every 3 weeks through Week 24, and every 12 weeks thereafter until Week 96. In Cohorts 1 and 3, participants receive CET until Week 78. Primary disease assessments (cystoscopy, urine cytology, transurethral resection of bladder tumor [TURBT], and magnetic resonance imaging/computed tomography) are made at baseline; subsequent cystoscopy and centrally read urine cytology are performed every 12 weeks through Year 2, every 24 weeks until end of Year 3, and in Year 4 and Year 5 in accordance with institutional standards of care. TURBT is conducted at 24 and 48 weeks. The primary end point for the 3 cohorts is overall CR rate at any time point. Secondary end points include duration of response (ie, from time of first CR achieved to first evidence of recurrence, progression, or death [whichever is earlier] for participants who achieve a CR), overall survival, PK immunogenicity of cetrelimab, safety and tolerability, and patient-reported outcomes. Exploratory end points include incidence and time to cystectomy (measured from randomization to date of cystectomy), biomarkers, and health care resource utilization. This study opened in January 2021 and is enrolling participants at ≈165 study sites worldwide. Currently, the study is active in 13 countries with 12 participants enrolled as of September 12, 2021. Clinical trial information: NCT04640623.